NOG
protein-codingnoggin
Gene summary
The secreted polypeptide, encoded by this gene, binds and inactivates members of the transforming growth factor-beta (TGF-beta) superfamily signaling proteins, such as bone morphogenetic protein-4 (BMP4). By diffusing through extracellular matrices more efficiently than members of the TGF-beta superfamily, this protein may have a principal role in creating morphogenic gradients. The protein appears to have pleiotropic effect, both early in development as well as in later stages. It was originally isolated from Xenopus based on its ability to restore normal dorsal-ventral body axis in embryos that had been artificially ventralized by UV treatment. The results of the mouse knockout of the ortholog suggest that it is involved in numerous developmental processes, such as neural tube fusion and joint formation. Recently, several dominant human NOG mutations in unrelated families with proximal symphalangism (SYM1) and multiple synostoses syndrome (SYNS1) were identified; both SYM1 and SYNS1 have multiple joint fusion as their principal feature, and map to the same region (17q22) as this gene. All of these mutations altered evolutionarily conserved amino acid residues. The amino acid sequence of this human gene is highly homologous to that of Xenopus, rat and mouse. [provided by RefSeq, Jul 2008]
- SYNS1
- SYM1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~1.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008484
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0100521
Submitter: ClinGen
The NOG gene is located on chromosome 17 at 17q22 and encodes a secreted homodimeric glycoprotein called noggin that is essential for normal bone and joint development. NOG was first reported in relation to autosomal dominant NOG-related Symphalangism Spectrum Disorder in 1999 (Gong et al., 1999, PMID: 10080184). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, phenotypic variability, and inheritance pattern of the five disease assertions. For these reasons, the following diseases have been lumped into one entity; proximal symphalangism (MIM 185800), multiple synostoses syndrome 1 (MIM 186500), tarsal-carpal coalition syndrome (MIM 186570), stapes ankylosis with broad thumbs and toes (MIM 184460), and brachydactyly type B2 (MIM 611377). The new term encompassing these five overlapping clinical syndromes is NOG-related Symphalangism Spectrum Disorder (NOG-SSD) (MONDO: 0100521, Potti et al., 2011, PMID: 21538686). NOG-SSD is characterized by proximal symphalangism, conductive deafness caused by stapes ankylosis, ocular abnormality such as hyperopia and strabismus, and characteristic facial features including a broad, tubular-shaped nose and a thin upper vermilion (PMID: 21538686). The term NOG-SSD aids in the clinical diagnosis and evaluation of affected individuals.Two missense, five frameshift, and three nonsense variants reported in ten probands in four publications (PMID: 12089654, 15699718, 21358557, 25241334) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function which leads to misfolding, decreased stability, decreased affinity to bone morphogenic proteins (BMPs), or reduced/undetectable secretion of noggin. This gene-disease relationship is also supported by biochemical data, functional alteration assay, and mouse animal models (PMID: 9603738, 12478285, 1156247, 18096605). In summary, there is definitive evidence supporting the relationship between NOG and autosomal dominant NOG-related Symphalangism Spectrum Disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date July 5, 2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0008519
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0100521
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0100521
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008511
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012658
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0017923
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008521
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008519
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Craniofacial; Musculoskeletal
Intervention: Audiologic/Otolaryngologic
Rationale: Hearing impairment may be prelingual in some individuals, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development
Comments: Some conditions may be frequently recognizable based on clinical manifestations
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NOG variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005450.6. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 25 | 40 | 65 | |||
| missense | 14 | 16 | 124 | 5 | 2 | 161 |
| nonsense | 8 | 5 | 13 | |||
| start loss | 1 | 1 | ||||
| frameshift | 11 | 7 | 18 | |||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 34 | 28 | 149 | 45 | 2 | 258 |
Highest pathogenic variant AF is 0.0000013721976
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005441.1 | 1 | MANE Select | |
| Ensembl | ENSP00000328181.4 | 1 | MANE Select |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| nog1 | Danio rerio | Structure: Meckel's cartilage Quality: decreased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- TGF-beta signaling pathway - Homo sapiens (human)
- Bone Morphogenic Protein (BMP) Signalling and Regulation
- Cardiac Progenitor Differentiation
- Hair Follicle Development- Induction (Part 1 of 3)
- Differentiation Pathway
Biological Process
- negative regulation of transcription by RNA polymerase II
- skeletal system development
- osteoblast differentiation
- in utero embryonic development
- endoderm formation
Molecular Function
- protein binding
- cytokine binding
- protein homodimerization activity
Cellular Component
- extracellular region
- extracellular space
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000332822
- Coding exons
- 1
- Length
- 1892
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.32 | 94 | 137 | 0.684 | 0.00000614 | 1459 |
| Missense (PolyPhen) | 17 | 55.005 | 0.30906 | 578 | ||
| Synonymous | -0.560 | 72 | 66.2 | 1.09 | 0.00000306 | 505 |
| Loss of Function | 2.48 | 0 | 7.17 | 0.00 | 3.10e-7 | 69 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Inhibitor of bone morphogenetic proteins (BMP) signaling which is required for growth and patterning of the neural tube and somite. Essential for cartilage morphogenesis and joint formation. Inhibits chondrocyte differentiation through its interaction with GDF5 and, probably, GDF6 (PubMed:21976273, PubMed:26643732). {ECO:0000269|PubMed:12478285, ECO:0000269|PubMed:21976273, ECO:0000269|PubMed:26643732}.;
- Disease
- DISEASE: Symphalangism, proximal 1A (SYM1A) [MIM:185800]: A disease characterized by the hereditary absence of the proximal interphalangeal joints. Distal interphalangeal joints are less frequently involved and metacarpophalangeal joints are rarely affected whereas carpal bone malformation and fusion are common. In the lower extremities, tarsal bone coalition is common. Conductive hearing loss is seen and is due to fusion of the stapes to the petrous part of the temporal bone. {ECO:0000269|PubMed:10080184, ECO:0000269|PubMed:11846737, ECO:0000269|PubMed:11857750, ECO:0000269|PubMed:15770128}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Multiple synostoses syndrome 1 (SYNS1) [MIM:186500]: A bone disease characterized by multiple progressive joint fusions that commonly involve proximal interphalangeal, tarsal-carpal, humeroradial and cervical spine joints. Additional features can include progressive conductive deafness and facial dysmorphism. {ECO:0000269|PubMed:10080184, ECO:0000269|PubMed:20503332}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Tarsal-carpal coalition syndrome (TCC) [MIM:186570]: Autosomal dominant disorder characterized by fusion of the carpals, tarsals and phalanges, short first metacarpals causing brachydactyly, and humeroradial fusion. TCC is allelic to SYM1, and different mutations in NOG can result in either TCC or SYM1 in different families. {ECO:0000269|PubMed:11545688}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Stapes ankylosis with broad thumb and toes (SABTS) [MIM:184460]: An autosomal dominant disorder characterized by hyperopia, a hemicylindrical nose, broad thumbs, great toes, and other minor skeletal anomalies but lacked carpal and tarsal fusion and symphalangism. {ECO:0000269|PubMed:12089654}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Brachydactyly B2 (BDB2) [MIM:611377]: A form of brachydactyly characterized by hypoplasia/aplasia of distal phalanges in combination with distal symphalangism, fusion of carpal/tarsal bones and partial cutaneous syndactyly. {ECO:0000269|PubMed:17668388}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.729
Intolerance Scores
- LoFtool
- 0.0709
- RVIS EVS
- 0.35
- RVIS percentile EVS
- 73.97
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.651
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |